S-aralkylamino-z-dialkylaminoben



Patented Aug. 4, 1953 S-ARALKYLAMINO-B-DIALKYLAMINOBEN- ZO[a]PHENOXAZINECOMPOUNDS AND METHOD OF PREPARING SAME Moses L. Crossley, Plainfield,and Paul F. 'Dreis- I bach, Somerville, N. J assignors to AmericanCyanamid Company, New York, N. Y., a corporation of Maine No Drawing.Application November 4, 1950, Serial No. 194,182

6 Claims. (Cl. 260-244) This invention relates to 5-aralkylamino-9-dialkylaminobenzo[alphenoxazines, and processes of preparing the same.

5-benzylamino 9 diethylaminobenzoEalphenoxazine has been prepared as ablue dye. It has some activity against tubercle bacilli. It issubstantially useless for differential fat staining in vivo. Accordingto the present invention it has been found that a remarkable increase inantitubercular activity is obtained when one of the alkyl groups on the9-amino nitrogen is from 3-6 carbon atoms, and the other from 2-5 carbonatoms, reaching a very sharp peak when the two alkyl groups have 4carbon atoms. The longer chain alkyl groups on the 9-nitrogen also endowthe compounds with the ability to preferentially stain fatty tissue inliving animals; such as, for example, mice, and renders the compoundsuseful for biological studies. A very effective differential staining ispossible with the compounds of the present invention.

The compounds of the present invention may be represented in the form oftheir free bases by the following formula l \N- NCHzRa R;

where R1 is alkyl of 3 to 6 carbon atoms; R2 is alkyl of 2 to carbonatoms; R3 is phenyl or phenyl substituted with halo, alkyl, alkoxy oralkylenedioxy, and R4 and R5 are hydrogen or lower alkyl.

Since the compounds are bases they are capable of forming addition saltswith ordinary strong acids such as hydrochloric, hydrobromic, nitric,sulfuric, phosphoric, etc. In the salt form several formulations havebeen proposed. In the present application, we prefer to use thefollowing form which seems to be most likely from experimental evidence:

O NHCHaRa Ba x X representing the anion of the acid and the Rs havingthe same significance as above. It should be understood that theinvention is not intended to be limited to any theory of the exactstructural form of the addition salts. The

' somewhat with R3.

2 formula given is merely the one used for convenience. Otherformulation in which the anion is connected to the oxygen of the ringhave also been proposed.

The following table gives a representation of the relativeanti-tuberculosis activity of three typical series of compounds whenadministered to the mice infected with a bovine strain of tubercle Themost active compounds; such as those in which R1 and R2 have 3 and 4carbon'atoms, possess an activity in mice markedly greater than that ofstreptomycin; The antitubercular activity depends primarily on the totalnumber of carbon atoms representedby R1 andRz. Thus while it will beseen that, in general, the dihexylaminocompounds are inferior to, or nobetter than, the diethylamino compounds, compounds such as ethylhexyl orpropylhexyl show activitie which are considerably higher. As will appearfrom the table, the activity will vary Other typical compounds whichalso show th'e'in'creased activities in their series, are those in whichR3 is Q 1 I C Slightly less active are compounds in which R3 is and Thevery sharp peak in antitubercular activity for theB-dibutylaminocompounds is quite different from. the case presented. bythe corresponding S-arylamino compounds which are described and claimedin the copending application,

Serial No. 109,625, filed August 10, 1949, now

Patent No. 2,528,862, in which the sharp peak occurred with thedipropylamino compound, the dibutylamino compound being no better thanthe diethyl. It is not known why an entirely different point of maximumactivity is to be found in the compounds of the present invention. Thevariation of antitubercular activity with structure modification isdiiferent with the two series. It is not known why there should be thedifferent sharp peak of maximum activity in the two different series andit is not intended to limit the present invention to any theory of whycertain structures should have the surprisingly high antitubercularactivity. Also, it is not known why the compounds of the presentinvention can be used effectively either in the form of their free basesor salts for diflerential tissue staining in vivo simply by includingthe compounds in the animals food. The mechanism by which thisdifierential tissue staining occurs is not at present known except thatitseems certain that part, at least, of the color i carried in the bloodstream. The invention is therefore likewise not limited to any theory ofwhy the effective differential staining takes place, through thediscovery has resulted in the addition of an important research tool inanimal experimentation.

The products of the present invention may be prepared by two processesof ring closure resulting in the first instance, in the production ofthe addition salts of the bases with acids, the free base itself beingreadily prepared therefrom by the action of an alkaline agent. The twomechanisms will be illustrated generally by equations showing thepreparation of the -benzylamino compounds.

OH O.-

R: Cl

It will be noted that these two processes involve a ring closurereaction using a meta-hydr substituted dialkylaniline with .anitrogen- 4containing radical ortho to the hydroxy group. When thenitrogen-containing group is amino, the other reactant is an o-quinonederivative of a substituted naphthylamine, whereas when thenitrogen-containing group is a nitroso or oximino group, the substitutednaphthylamine itself is used. In each case, the condensation reaction isaccompanied by the elimination of water. The first method is preferredfor the preparation of most of the compounds because the simpleN-aralkyl-naphthylamine is used which is easier to prepare than thecorresponding 0- quinones.

The invention will be described in greater detail in conjunction withthe following specific examples, the parts being by weight unlessotherwise specified.

EXAMPLE 1 2-nitroso-5-dipropylaminophenol hydrochloride To 218 parts ofm-aminophenol are added 300 parts of ethyl alcohol forming a darkcolored slurry. To this slurry are added 369 parts of npropyl bromideand the whole is then heated to a gentle reflux for approximately 5hours. After removal of alcohol and some unchanged propyl bromide bydistillation, the residue is poured into water and treated with soda ashto cause separation of the aminophenol derivatives. The oil layer istaken up in ether, the ether solution is dried and the ether is finallyremoved by distillation leaving a residue to which is added the alcoholand unchanged propyl bromide removed from the original reaction mixtureplus 123 parts of fresh propyl bromide. The resulting solution is thenheated to the reflux temperature with stirring for approximately 22hours, and finally alcohol and a small amount of unchanged propylbromide are again removed by distillation.

The residue is poured into 1000 parts of water and the mixture is madealkaline by the addition of solid soda ash. The product, which ispresent as a water insoluble oil, is removed and purified by a vacuumdistillation giving the purified m-dipropylaminophenol in the form of astraw colored viscous liquid which shows a boiling point of about 132 to133 C. at 3 mm. pressure. Upon exposure to air, this liquid acquires adeep red color.

This aminophenol derivative is dissolved in 880 parts of concentratedhydrochloric acid and to the solution is added gradually a solution of103 parts of sodium nitrite in 210 parts of water, the temperature ofthe whole mixture being kept below about 10 C. throughout the addition.After the reaction is complete the water-soluble orange-colored solidwhich forms, consisting of the hydrochloride of the p-nitroso derivativeof m-dipropylaminophenol, is removed by filtration, washed with dilutehydrochloric acid and dried. This intermediate product may be used asformed or may be purified, giving an orangecolored solid with a meltingpoint of about 151- 152 C.

EXAMPLE 2 5-benzylamino-9-dipropylaminobenzo [alphenoxazonium chlorideTo a suspension of 117 parts of N-benzyl-alpha-naphthylamine in 600parts of ethyl alcohol are added 194 parts of2-nitroso-5-dipropylaminophenol hydrochloride plus a few drops ofconcentrated hydrochloric acid. The whole is then heated to the refluxtemperature with stirring for a total period of about three hours duringwhich time the color changes through brown and green to an intense blue.

After cooling, the precipitated glistening green product consisting ofthe chloride salt, is separated by filtration and is purified byrecrystallization from acetic acid, using at least 2.5 parts of aceticacid for each part of product.

The base is prepared by treating an ethyl alcohol slurry or suspensionof the chloride salt with aqueous ammonium hydroxide solution. The baseis obtained as a reddish brown solid exhibiting a reddish color in ethylalcohol solution.

An ethyl alcohol solution of the chloride salt shows an intense bluecolor with a maximum absorption at about 645 millimicrons measuredspectrophotometrically. An ethyl alcohol solution of the base shows ared color with a maximum absorption at about 518 millimicrons by aspectrophotometric determination.

EXANIPLE 3 5 (4 methylbenzylamino)-9-dipropylaminobenzomlphenorazomumchloride EXAIVIPLE4 5-(4 chlorobenzylamino)-9dipropylaminobenzoialphenomazonium chloride The procedure of Example 2is followed but 134 parts of N-(p-chlorobenzyl)-alpha-naphthylamine areused in place of 117 parts of N-benzyl-alpha-naphthylamine.

The addition of excess ammonium hydroxide solution to the blue alcoholicsolution of the salt of the product precipitates the red-brown baseform.

EXAMPLE5 5 (3,4-methyleneclioxybenzylamino) 9 dipropylaminobenzo [a]phenorazonium chloride The procedure of Example 2 is followed but 139parts of N-(3,4-methylenedioxybenzyl)-a1- pha-naphthylamine are used inplace of 117 parts of N-benzyl-alpha-naphthylamine.

The N-(3,4 methylenedioxybenzyl) alphanaphthylamine which has a meltingpoint of about 65 to 67 C. is prepared as follows:

To a suspension of 273 parts of N-(3,4-methylenedioxybenzal)-alpha-naphthylamine in 8000 parts of methyl alcohol are added in smallportions, 420 parts of magnesium chips, the whol being kept at thereflux temperature. The excess methyl alcohol is then removed bydistillation and the benzylnaphthylamine derivative is obtained bytreatment with acetic acid and water which causes the magnesiumcompounds to be dissolved leaving the water-insoluble N-(3,4-methylenedioxybenzyl) alpha-naphthylamine. This is purified bycrystallization from alcohol.

The N-(3,4 methylenedioxybenzal) alphanaphthylamine used as startingmaterial is formed by treating equimolar quantities. of piperonal andalpha-naphthylamine in ethyl alcohol solution at the reflux temperaturefor about one-half hour. The anil separates on heating and has a meltingpoint of about to 111 C.

EXAMPLE 6 5-(2-chlorobenzylamino) 9 dipro-pylaminobenzo a] phenoxazoniumchloride The procedure of Example 2 is used but 134 parts of N(o-chlorobenzyl)-alpha-naphthylamine are used in place of 117 parts ofN-benzylalpha-naphthylamine.

In alcohol or acetic acid solution, the product shows a blue color.Addition of ammonium hydroxide solution to an alcoholic solution of thesalt gives a brownish red solution of the base which is recovered in thesolid form as a dark red-brown material.

The o-chlorobenzylnaphthylamine which is used in this preparation has amelting point of about 110 to 112 C. and is prepared by the reduction ofN-(o-chlorobenzal) -alpha-naphthylamine with magnesium chips in methylalcohol using a procedure similar to that described under Example 5 forthe preparation of N-(3,4- methylenedioxybenzyl) -alpha-naphthylamine.

7 EXAMPLE'Z 2-amino-5-dipropylaminophenol dihydrochloflde To an acidicsolution of 1350 parts of stannous chloride dihydrate are addedgradually 7'76 parts of 2-nitroso-5-dipropylaminophenol hydrochloride.The mixture is agitated and the reduction is carried out at about roomtemperature or below.

After passing hydrogen chloride gas into the mixture, the whitecrystalline solid is removed by filtration. The separation of theproduct from the tin salt complex is effected by treatment of an aqueoussolution of the complex with hydrogen sulfide gas which causesprecipitation of the tin as tin sulfide.

The metal-free aqueous solution is then concentrated by distillation,yielding a light solid product which after removal by filtration ispurified by crystallization from ethyl alcohol to give thedihydrochloride in the form of snow white crystalline material. Thisdecomposes when heated to temperatures somewhat above 200 C. andgenerally acquires a bluish color upon exposure to the atmosphere.

EXAMPLE 8 -benzylamino9-dipropylaminobenzo [a] phenoxazonium chloride Toapproximately 3000 parts of ethyl alcohol are added 281 parts of2-amino-5-dipropylaminophenol dihydrochloride and 263 parts of 4-benzylamino-1,2-naphthoquinone. The mixture is heated to the refluxtemperature with occasional agitation for about 1%; to 2 hours. Thereresults an intensely blue solution from which precipitates on cooling, aglistening green solid product. This crystalline material which is achloride salt, is removed by filtration and may be purified byrecrystallization from acetic acid.

The green product is somewhat soluble in ethyl alcohol to which itimparts a deep blue color. The base compound is formed by treatment of aslurry of the chloride salt in alcohol with excess ammonium hydroxide.The red-brown solid base at times tends to decompose on storage and thesalt form such as the chloride, is therefore more easily handled. Theproduct here is identical with that obtained by using the processdescribed under Example 2.

EXAMPLE 9 3-dibutylamz'nophenol To 218 parts of m-aminophenol are added300 parts of ethyl alcohol forming a dark-colored slurry. To this slurryare added 411 parts of nbutyl bromide and the whole is then heated to agentle reflux for approximately 5 hours. After removal of alcohol andsome unchanged butyl bromide by distillation, the residue is poured intowater and treated with soda ash to cause separation of the aminophenolderivatives. The oil layer is taken up with ether, the ether solution isdried and the ether is finally removed by distillation, leaving aresidue to which is added the alcohol and unchanged butyl bromideremoved from the original reaction mixture plus 137 parts of fresh butylbromide. The resulting solution is then heated to the reflux temperaturewith stirring for approximately 22 hours, and finally alcohol and asmall amount of unchanged butyl bromide are again removed bydistillation.

The residue is poured into. 1000 parts of water and the mixture is madealkaline by the addition of solid soda ash. The product, which ispresent as a water insoluble oil, is removed and purified by a vacuumdistillation giving the purified product in the form of a straw-coloredviscous liquid with a boiling range of approximately 173 to 176 C. at 6mm. pressure. Exposure of this m-dibutylaminophenol to the atmospherecauses it to acquire a deep red color.

EXAMPLE 10 S-benzylamino-9-dibutylaminobenzo [a] phenorazonium chlorideNHCH2- O A solution of 88.4 parts of m-dibutylaminophenol in 60 partsethyl alcohol and parts of concentrated hydrochloric acid is cooled toabout 5 C. A paste prepared from 30.4 parts of sodium nitrite and about2 parts of water is then added to the solution with stirring in smallportions over a period of about one hour, the temperature beingmaintained at 5 C. throughout the addition. The resulting red-orangemixture is stirred another one-half hour and the suspended sodiumchloride is removed by filtration and discarded.

The filtate is slowly added to a solution of 62 parts ofN-benzyl-alpha-naphthylamine in 400 parts of ethyl alcohol and the wholeis heated to the reflux temperature with stirring for two hours. Thegreen solid product which forms on cooling this reaction mixture isremoved by filtration and purified by recrystallization from about 500parts of ethyl alcohol. This product, which is a chloride salt, isobtained as bright green crystalline material which gives an intenseblue color in alcohol solution; This shows a maximum absorption at about647 millimicrons measured spectrophotometrically. An ethyl alcoholsolution of the freshly prepared base shows a maximum absorption atabout 519 millimicrons.

The base of this product is formed by the addition of ammonium hydroxidesolution to an alcoholic suspension or solution of the above chloride,the base being obtained as a red-brown solid. This base in the solidform tends to undergo decomposition and the salt form such as thechloride is therefore preferred if the material is to be stored for anyappreciable length of time.

EXAMPLE ll 5- (4-methylbenzylamin0) -9-dibutylaminobenzolalphenomazoniumchlor de This product and the corresponding base are prepared by theprocedure described under Example 10 except that 65 parts ofN-(p-methylbenzyl) -alpha-naphthylamine are used instead of. 62 parts ofN-benzyl-alpha-naphthylamine.

m tts EXAIVLPLE 12 (4-chlorobenzylamino) -9-dibutylaminobenzomlphenoarazonium chloride N l (olrmmg gmcm-ci This product and thecorresponding base are prepared by the procedure described under Example10 except that 71 parts of N-(p-chlorobenzyl) -a1pha-naphthy1amine areused instead of 62 parts of N -benzl-alpha-naphthylamine.

EXAMPLE 13 5- (3,4-methylenediorcybenzylamino) -9-dibutylaminobenaoEa]phenozrazonium nitrate O---CH| A solution of 88.4 parts ofm-dibutylaminophenol in 60 parts of ethyl alcohol and 120 parts ofconcentrated hydrochloric acid is cooled to about 5 C. A paste preparedfrom 30.4 parts of sodium nitrite and about 2 parts of water is thenadded to the solution with stirring in small portions over a period ofabout one hour the temperature being maintained at 5 C. throughout theaddition. The resulting red-orange mix- 1 ture is stirred anotherone-half hour and the suspended sodium chloride is removed by filtrationand discarded.

The filtrate is slowly added to a solution of 73 parts ofN-(3,4-methylenedioxybenzyl)-alphanaphthylamine in 400 parts of ethylalcohol and the whole is heated to the reflux temperature with stirringfor two hours. After cooling the reaction mixture, about 30 parts ofnitric acid are added with stirring, causing the nitrate salt toprecipitate.

After removal by filtration, the nitrate is purified byrecrystallization from 1000 parts of ethyl alcohol.

The base of this product is obtained by the addition of ammoniumhydroxide solution to a slurry of the nitrate in alcohol.

EXAMPLE 14 3-diamylamznophenol A solution of 109.1 parts ofmeta-aminophenol, 151 parts of amyl bromide and 150 parts of alcohol isrefluxed for a period of about 4 hours with stirring. 151 parts of amylbromide, 106 parts of soda ash and 200 parts of water are then added andthe mixture is refluxed about 16 hours longer. The dark oily product isseparated from the water layer, and distilled. There is obtained 221parts of product boiling at about 170-189 C. at 5 mm. with a refractiveindex of n =1.5253.

10 EXAMPLE 15 s-benzymmim-s-diam zammobenso[aiphenoxazonium chloride Asolution of 24.9 parts of m-diamylaminophenol, 65 parts of alcohol and30 parts of concentrated hydrochloric acid is cooled to about 5 C., andtreated with 7.6 parts of sodium nitrite added over a period of about 1/2 hours. After stirring for hour longer the mixture is filtered toremove the salt and then added to a solution of 15.4 parts ofN-benzyl-alpha-naphthylamine and parts of alcohol. The resultingsolution is refluxed for 4 hours and stirred for about 15 hours at roomtemperature, then cooled and filtered. The product is obtained as a darkred crystalline material after recrystallization from 50 parts of ethylalcohol. This product gives a blue solution in alcohol, and is insolublein water.

EXAMPLE 16 5 -benz1 Zamin0-Q-diamylaminobenzo[a] phenoxazine baseEXAMPLE 17 5- (4 -chlo1-obeneylamino) -9 -diamylaminobenzo [a]phenomazonium chloride This compound is prepared in a manner similar tothat described in Example 15 except that in this case 17.6 parts of N-(p-chlorobenzyl) -alphanaphthylamine are used instead of 15.4 parts ofN-benzyl-alpha-naphthylamine.

. The purified chloride salt is obtained; this dissolves in alcohol togive a blue solution.

11 EXAMPLE 1:;

- (4-chlorobenzylamino) -9-diamylaminobenzo [a] phenozcazine baseNCHz-G-Cl A mixture of 17.7 parts of 5-(4-chlorobenzylamino) 9diamylaminobenzo[alphenoxazonium chloride, prepared as described underExample 17, and 350 parts of alcohol is warmed gently and filtered; tothe filtrate are added 20 parts of concentrated ammonium hydroxidesolution, while stirring vigorously. After filtering, the brown-greenbase is obtained which melts at about Bi-75 C. This base is unstable andgradually decomposes toa black tarry mass with a foul odor.

EXAMPLE 19 5--(4-methylbenzylamino) -9-diamylaminobenzo a] phenoxazoniumnitrate A solution of 12.5 parts of m-diamylaminophenol, 35 parts ofethyl alcohol and parts of concentrated hydrochloric acid is cooled to 5C.

and treated with 3.8 parts of sodium nitrite over EXAMPLE 20 5-(st-methoxybenzylamino) -9-diamylaminobenzo a] phenorazom'um chloride Nwamn g NHCHr-O on;

A solution of 24.9 parts of m-diamylaminophenol, 65 parts of ethylalcohol and 30 parts of concentrated hydrochloric acid is cooled to 5 C.and treated with 7.6 parts of sodium nitrite over a period of about 2hours. After stirring an additional half-hour, the mixture is filteredto remove the salt and the filtrate is added to a solution of 17.4 partsof N-(p-methoxybenzyl) -alphanaphthylamine, and 100 parts of ethylalcohol. After refluxing for about an hour, and stirring at roomtemperaturefor about 15 hours the solution is allowed to stand. Thealcohol evaporates causing the product to solidify; this in insoluble inwater, slightly soluble in benzene, fairly soluble in dioxane andsoluble in alcohol.

EXAMPLE 21 3-ethylpropylaminophenol To a solution of 274 parts of3-ethy1aminophenol in 400 parts of ethyl alcohol are added 246 partspropyl bromide. The whole is heated to a temperature of about 70 to C.for five hours and is then poured into two liters of iced water.Suificient sodium carbonate is added to cause a slightly alkalinereaction and release the product from its hydrobromide. The product inthe form of a viscous oil is removed and distilled in vacuum forpurification. The light yellow oil obtained has a boiling point of about138 to 140 C. at 3 millimeters pressure.

EXAMPLE 22 2-nitr0so-5-ethylpropylaminophenol hydrochloride A solutionof 179 parts of 3-ethylpropylaminophenol in 570 parts of concentratedhydrochloric acid is cooled to about 5 C. and to it is added dropwisewith stirring a solution of 69 parts of sodium nitrite in parts ofwater. The addition takes about one hour and the reaction mixture iskept below about 10 C. throughout the addition.

After stirring for about one more hour, some precipitated sodiumchloride is removed by filtration. On further cooling, the nitrosohydrochloride precipitates and is removed by filtration. More of theorange-yellow crystalline product is obtained by concentration of themother liquor.

EXAMPLE 23 5-benzylamino-Q-ethylpropylaminobenzo [alphenoxazoniumchloride A solution containing 600 parts of ethyl alcohol, 117 parts ofN -benzyl-alpha-naphthylamine and '7 parts of concentrated hydrochloricacid is prepared and heated to its boiling point. To the warm solutionare added 184 parts of 2-nitroso- 5-ethylpropylaminophenolhydrochloride, prepared as described under Example 22 and the whole isthen heated to the reflux temperature with stirring for about threehours.

After cooling in an ice-bath, the product precipitates in the form of aglistening green solid. This is removed by filtration and purified byrecrystallization from about 2000 parts of acetic acid.

An intensely blue solution is formed by dissolving this chloride salt inethyl alcohol. Addition of an alkaline reagent to the solution causes acolor change to red with the liberation of the base.

'13 EXAMPLE 24 (4-chlorobenzylamino)-9-ethylpropylaminobenzolalphenowazonium chloride The procedure ofExample 23 is followed but 134 parts ofN-(4-chlorobenzyl)alpha-naphthylamine are used in place of 117 parts ofN-benzylalpha-naphthylamine.

EXAMPLE 25 m-Ethylhezcylaminophenol A solution of 109 parts ofm-aminophenol, 182 parts of n-hexyl bromide and 300 parts of ethanol isrefluxed for about 4 hours, then the alcohol is removed by distillationand the residue is poured into 700 parts of water. The mixture is madealkaline by the addition of soda ash, and the thick brown mass isseparated from the aqueous layer and dissolved in 300 parts of ethanol.120 parts of ethyl bromide are added and the solution is refluxed forabout 8 hours, then the alcohol is removed by distillation and theresidue is poured into 1000 parts of water. After making alkaline withsoda ash, the dark brown layer is separated from the aqueous layer andfractionally distilled. The product has a boiling point of about 165-185C. at about 5 millimeters.

EXAMPLE: 26

5 -benzylamino-9-ethylhexylaminobenzo[a] phenowazonium chloride Asolution of 22.1 parts of m-ethylhexylaminophenol, 65 parts of ethylalcohol and 30 parts of concentrated hydrochloric acid is cooled toabout 5 C. and treated with 7.6 parts of sodium nitrite added in smallportions during a period of 1 hours. After stirring about an hourlonger, the dark red mixture is filtered, to remove the salt, and thenadded to a refluxing solution'of 15.4 parts ofN-benzyl-alpha-naphthylamine and 100 parts of ethyl alcohol over aperiod of about 40 minutes. After refluxing for an additional hour andallowing to stand at room temperature for about 24 hours the mixture isfiltered. The product after recrystallizin from 300 parts of glacialacetic acid is obtained as a green crystalline solid, insoluble in waterand soluble in alcohol giving a blue solution.

EXAMPLE 27 Odin 4J1 NHCHr-Ol This compound is prepared in a mannersimilar to that described in Example 26 except that in this case 17.6parts of N-(p-chlorobenzyl) -alphanaphthylamine are used in place of the15.4 parts of N-benzyl-alpha-naphthylamine.

The green crystalline chloride is recrystallized from hot formic acidfor purification. It is insoluble in water, and soluble in alcoholgiving a blue solution.

EXAMPLE 28 3-ethylpropylamino-4-methylbenzene sulfomc acid product whichboils at about 218 to 221 C.

This ethylpropylamino derivative is then added gradually with stirringover about 2% hours to 2400 parts of 25 percent oleum cooled below 10 C.After stirring another hour, the whole is added to sufilcient ice togive a total volume of about 5000 parts. Addition of about 1500 parts of50 percent sodium hydroxide solution causes precipitation of thesulfonicacid derivative in the form of a white solid. This is removed byfiltration and recrystallized from about 2000 parts of water.

EXAMPLE 29 2 nitroso 4 methyl 5 ethylpropylaminophenol hydrochloride Ina stainless steel crucible, a melt of 705 parts of potassium hydroxideand 46 parts of water is prepared. With stirring, 514 parts of 3ethylpropylamino 4 methylbenzene sulfonic acid, prepared as describedunder Example 28 are then added over a ten-minute period, thetemperature of the mixture being kept at about 290 to 310 C. Before themixture has cooled below about 200 C., it is poured into a mixture ofice and water to give a total volume of about 4000 parts. Suflicienthydrochloric acid is added to cause an acid reaction and the mixture isfiltered to remove impurities. Enough solid sodium carbonate is thenadded to the filtrate to cause a slightly alkaline reaction. The oilwhich separates, containing the newlyformed phenol derivative, isremoved and distilled for further purification.

The 292 parts of this oil are then dissolved in 1500 parts of normalhydrochloric acid and the solution is cooled to below 10 C. A solutionof 69 parts of sodium nitrite in 200 parts of water is added graduallyat 10 C. and after stirring several hours more, the supernatant liquidis decanted from the thick dark product. This crude nitroso derivativeis taken up in ether and dried and then treated with 55 parts of asaturated alcoholic solution of hydrogen chloride. The solid orangenitroso derivative which forms, melts at about 134 C'., withdecomposition; this is purified by recrystallization from ethyl alcoholto give the purified yellowcolored hydrochloride.

15' EXAMPLE so 5 (4 chlorobenzylamino) 9 ethylpropylamino 10methylbenzowlphenozazonium chloride N l Q fi'fl CHr- O1 To a suspensionof 267 parts of N-(p-chlorobenzyl)-alpha-naphthylamine in 1500 parts ofethyl alcohol are added 488 parts of 2-nitroso- 4 methyl 5ethylpropylaminophenol hydrochloride, prepared as described in Example29. This is then heated to the reflux temperature for about four hoursand then the deep blue solution is cooled and kept under refrigeration.The product slowly separates and is removed in the form of a mixture ofgreen glistening solid along with some blue solid product. The purifiedchloride salt is obtained by recrystallization from acetic acid.

It is sufiiciently soluble in ethyl alcohol to form a deep bluesolution. Addition of aqueous ammonia solution causes liberation of thebase giving a reddish brown solution. Addition of a small excess ofhydrochloric acid to a blue alcoholic solution of the chloride saltcauses a loss of the blue color with the formation of a deepyellow-brown solution. The blue color of the monochloride salt is againregenerated by the partial neutralization with ammonium hydroxidesolution.

EXAMPLE 3].

5 benzylamino 9 ethylpropylamino 10- methylbenzola]phenoxazoniumchloride The procedure outlined under Example is followed except that233 parts 01' N-benzylalpha-naphthylamine are used in place of 267 partsof N-(p-chlorobenzyl)-alpha-naphthylamine.

We claim:

1. 5 aralkylamino 9 dialkylamino benzo- [alphenoxazine compoundsselected from the group consisting of free bases having the followingformula \N o CHaRs where R1 is an alkyl group having not less than 3 normore than 6 carbon atoms, R2 is an alkyl group having not less than 2and not more than 5 carbon atoms, R3 is selected from 5 the groupconsisting of phenyl, halogen substituted phenyl, lower alkylsubstituted phenyl, lower alkoxy substituted phenyl, and methylenedioxysubstituted phenyl, R4 and R5 are selected from the group consisting ofhydrogen and lower allwl radicals and addition salts of the bases withacids.

2. 9 di n butylamino 5 benzylamino benzoEalphenoxazine, having theformula:

Nomo1 04110 5. Addition salts of 9 di n butylamino- 5 pchlorobenzylamino benzoEalphenoxazine with strong acids.

6. 9 di n propylamino 5 p chlorobenzylamino benzolalphenoxazine, havingthe formula:

CJH7

MOSES L. CROSSLEY. PAUL F. DREISBACH.

References Cited in the file of this patent UNITED STATES PATENTS NameDate Crossley et a1. Nov. '7, 1950 OTHER REFERENCES Sloviter Science,-vol. 110 (December 1949), pp. 687-688.

Number

1. 5 - ARALKYLAMINO - 9 - DIALKYLAMINO BENZO(A)PHENOXAZINE COMPOUNDSSELECTED FROM THE GROUP CONSISTING OF FREE BASES HAVING THE FOLLOWINGFORMULA